Crystallization and precipitation processes are known in the art, and are widely used in the chemical and pharmaceutical industries. Crystallization and precipitation processes are particularly prevalent in the pharmaceutical industry because over 90% of pharmaceutical products contain an active ingredient in particulate, generally crystalline, form. Properties of the crystallized product that are important include crystal size distribution (CSD), which generally should be as narrow as possible, and crystal shape/habit. These properties are determined by a variety of factors, such as crystallization technique employed, operating conditions, and choice of solvent.
Generally, there are four methods to induce crystallization: cooling, solvent removal, antisolvent addition, and chemical reaction (precipitation). The method of inducing crystallization generally dictates the type of process equipment utilized. Crystallization is generally carried out in stirred vessel devices, batch or continuous, in which perfect mixing of the slurry is presumed. One such type of continuous or batch type of stirred tank crystallizer is a Mixed Suspension Mixed Product Removal (MSMPR) crystallizer. MSMPR crystallizers are generally disadvantaged by poor mixing, fouling of heat transfer areas, small heat transfer area/volume ratio, and problems with scale-up. Furthermore, these conventional crystallization devices and methods are generally disadvantaged by not being able to meet the targets of a narrow CSD and a small mean crystal size due to imperfect mixing and non-uniform conditions inside the crystallizer. Conventional cooling crystallization devices are also disadvantaged by both nucleation and crystallization phenomena taking place simultaneously in the same vessel. In stirred vessels, continuous, batch or semi-batch, nucleation and growth occur in the same device, and therefore high supersaturation levels cannot be used due to severe incrustation of the cooling surfaces with a corresponding loss in performance.
In an effort to overcome these problems, two approaches have been investigated and/or undertaken. The first approach is to improve existing facilities by applying improved monitoring techniques that can lead to better prediction and control of the applied supersaturation, and hence better control of the final CSD. This approach is limited in performance because well-mixed crystallizers are intrinsically inclined towards a spectrum of local conditions in time and space, and consequently a relatively broad CSD.
The second approach is to develop new crystallization techniques where supersaturation can be created and depleted on a microscale, resulting in a narrow CSD and a small crystal size. The impinging-jet mixer technique is one such technique where two high velocity streams are brought into contact to effect high nucleation rates, followed by growth in a well-mixed vessel or a tubular precipitator. Other approaches that have been undertaken include emulsion crystallization, and precipitation with supercritical fluids.
Hollow fiber polymeric membrane devices have typically been used to prevent crystal formation. However, more recently, polymeric membranes have been used as a means of inducing crystallization and, in particular, as a means for producing crystals of a desired CSD and/or crystal shape through supersaturation creation and control. For example, reverse osmosis has been recognized as a crystallization technique involving solvent removal; however, reverse osmosis is disadvantaged by a high percentage of crystals remaining inside the reverse osmosis module resulting in fouling problems, pore blockage, a decrease in solvent flux, and generation of a supersaturation level with time. Reverse osmosis is also disadvantaged by the requirement of high operating pressures and the poor solvent resistance of reverse osmosis membranes.
Membrane distillation is another membrane technique involving solvent removal, but is also disadvantaged by fouling and pore blockage. Membrane distillation is also disadvantaged by a decrease in flux with increased feed concentration, and is generally suitable only for aqueous solutions due to wetting of the hydrophobic membrane pores by organic solvents.
Despite efforts to date, a need remains for cooling crystallizers that yield a higher heat transfer area/volume ratio, less fouling, improved temperature control, higher nucleation rates, smaller crystals and narrower crystal size distributions. These and other needs are advantageously satisfied by the systems, apparatus and methods disclosed herein.